Bicyclic derivatives of 1, 4- dihydropyridine

ABSTRACT

1,4-Dihydropyridines bearing carbonyl functions in the 3- and 5positions, being optionally substituted by lower alkyl in the 6position, being substituted in the 4-position by lower alkyl, phenyl, substituted phenyl or a heterocyclic group, and being fused through the 1- and 2-positions to a five, six or seven membered cycloalkyl ring, one methylene group of which can be replaced by sulfur, oxygen imino or alkylimino, are antihypertensive agents and coronary vessel dilators. The compounds, of which 6-methyl-4-(3-nitrophenyl)-1,2pentamethylene-1,4-dihydropyridine-3,5 -dicarboxylic acid 3,5diethyl ester is a representative embodiment, are prepared through condensation of an ylideneacetoacetic acid ester and a cyclic enamino carbonyl derivative.

llirited States Patent [191 Meyer et ai.

[ Dec. 24, W74

BIICYCLIC DERIVATIVES OF ll, 4- DlIHYlDROlPYRIDllNE Inventors: Horst Meyer; Friedrich Bosse'rt,

both of Wuppertal-Elberfeld; Wulf Vater, Opladen; Kurt Stoepel, Wuppertal-Vohwinkel, all of Germany Assignee: Bayer Aktiengesellschaft,

Leverkusen, Germany Filed: Feb. 28, 1973 Appl. No.: 336,477

Foreign Application Priority Data Sept. 12, 1972 Germany 2210633 us. (:1 260/2948 c, 260/2564 R, 260/2565 R, 260/283 CN, 260/283 s, 260/287 R, 260/289 R, 260/294.9, 260/295.5 B, 260/296 H, 260/297 B, 4 24/25 1 424/258, 424/266 int. Cl c076 31/50 Field 6r Search... 260/295.5 B, 294. c, 297 B [56 References Cited UNITED STATES PATENTS 3,784,600 1/1974 Strandtmann et al 260/2948 C Primary Examiner-Alan L. Rothman [57] ABSTRACT 1,4-Dihydropyridines bearing carbonyl functions in the 3- and 5-positions, being optionally substituted by lower alkyl in the 6-position, being substituted in the 4-position by lower alkyl, phenyl, substituted phenyl or a heterocyclic group, and being fused through the land 2-p0sitions to a five, six or seven membered cycloalkyl ring, one methylene group of which can be replaced by sulfur, oxygen imino or alkylimino, are antihypertensive agents and coronary vessel dilators. The compounds of which 6-methyl-4-(3-nitro l,2-pentamethylene-l ,4-dihydropyridine-3 ,5-

dicarboxylioacid 3,5-diethyl ester is a representative embodiment, are prepared through condensation of an ylideneacetoacetic acid ester and a cyclic enamino carbonyl derivative.

16 Claims, N0 Drawings IBICYCLIC DERIVATIVES OF 1,4- DII-IYDROPYRIDINE DETAILED DESCRIPTION The present invention pertains to bicyclic derivatives of 1,4-dihydropyridine, to processes for their production and use and to pharmaceutical compositions containing such compounds and useful as antihypertensive agents and coronary vessel dilators.

In particular, the present invention pertains to compounds of the formula:

wherein R is hydrogen or lower alkyl;

each of R and R independnet of the other, is lower alkyl or the group OR', in which R is a straightchain, branched or cyclic, saturated or unsaturated, aliphatic hydrocarbyl o'r oxyhydrocarbyl, the carbon chain of which is optionally interrupted by one or two oxygen atoms; R is a saturated or unsaturated, straight-chain, branched or cyclic hydrocarbyl; aryl optionally carrying l, 2 or 3 substituents selected from the group con-' sisting of lower alkyl, lower alkoxy, aziclo, halogen, nitro, nitrile, trifluoromethyl, carbo(lower alkoxy), lower alkylsulfonyl, lower alkylsulfinyl or lower alkylthio; or a member selected from the group consisting of naphthyl, quinolyl, isoquinolyl, pyridyl, pyri'midyl, thenyl, furyl and pyrryl, said member optionally carrying-a lower alkyl, lower alkoxy or halogeno substituent;

X is CH -NR in which R is hydrogen or lower alkyl, S-, or O; and

m is 2, 3 or 4.

A preferred class of the foregoing compounds are those of the formula: W

branched or straight hydrocarbon chain containing from 1 to 6 carbon atoms. Representative of such lower alkyl groups are thus methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl, tert. butyl, pentyl, isopentyl, neopentyl, tert. pentyl, hexyl, and the like.

The term lower alkenyl denotes a univalent branched or straight hydrocarbon chain containing from 2 to 6 carbon atoms and nonterminal ethylenic unsaturation as, for example, vinyl, allyl, isopropenyl, Z-butenyl, 3-methyl2-butenyl', Z-pentenyl, 3-pentenyl, 2-hexenyl, 4-hexenyl, and the like.

The term lower alkynyl denotes a univalent branched or straight hydrocarbon chain containing from 2 to 6 carbon atoms and nonterminal acetylenic unsaturation as, for example, ethynyl, 2-propynyl,.4-pentynyl, and the like.

The term lower alkoxy denotes a straight or branched hydrocarbon chain bound to the remainder of the molecule through an ethereal oxygen atoms as, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,

, the molecule through a divalent sulfur as, for example,

methylthio, ethylthio, propylthio, isopropylthio, butylthio, and the like.

The term halogen denotes the substituents fluoro,

chloro, bromo and iodo.

As indicated, the present invention also pertains to the physiologically acceptable non-toxic acid addition salts of these basic compounds. Such salts include those derived from organic and inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methane sulphonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embonic acid, enanthic acid, and the like.

According to the present invention, the foregoing compounds are prepared by reacting a dicarbonyl compound of the formula:

COR

ooR

wherein R, R and R are as herein defined, with a cyclic enamino carbonyl compound of the formula:

in which R, X and m are as herein defined. The condensation proceeds smoothly in good yields simply by heating the two components, generally in the presence of an inert organic solvent such as methanol, ethanol, propane] and similar alkanols, ethers such as dioxane and diethyl ether, glacial acetic acid, pyridine, dimethylformamide, dimethylsulfoxide, acetonitrile and the like. The reaction is conducted at temperatures of from 20 to 250C, conveniently at the boiling point of the solvent, and while elevated pressure may be utilized, normal atmospheric pressure is generally satisfactory. The reactants are employed insubstantially equimolar amounts. The dicarbonyl reagent can be uitlized as such or generated in situ by the reaction of an aldehyde of the formula R CH and a B-dicarbonyl compound of the formula R COCH COR Many of the dicarbonyl compounds utilized as one of the reactants are known to the art and the others can either be generated in situ as herein described or prepared according to methods well known to the art, see for example Org. Reaction XV, 204 et seq. (I967). Typical of this reactant are the following compounds:

benzylideneacetoacetic acid methyl ester, ethylideneacetoacetic acid methyl ester, isopropylideneacetoacetic acid methyl ester, 2-nitrobenzylideneacetoacetic acid methyl ester, Z-nitrobenzylideneacetylacetone, benzylideneacetylacetone, 3-nitrobenzylideneacetoacetic acid methyl ester, 3-nitrobenzylideneacetoacetic acid propargyl ester, 3-nitrobenzylideneacetoacetic acid allyl ester, 3-nitrobenzylideneacetoacetic acid B-methoxyethyl ester,

3-nitrobenzylideneacetoacelic acid B-ethoxyethyl esacid 2-methylmercaptobenzylideneacetoacetic acid isopropyl ester, 2-sulphineylmethylbenzylideneacetoacetic acid ethyl ester, 2-sulphonylbenzylidenemethylacetoacetic acid allyl ester, 4-sulphonylmethylbenzylideneacetoacetic acid ethyl ester, naphth-l-ylideneacetoacetic acid methyl ester, naphth-l-y|ideneacetoacetic acid ethyl ester, naphth-2-ylideneacetoacetic acid ethyl ester, Z-ethoxynaphth-l -ylideneacetoacetic acid methyl ester, Z-methoxynaphthl -ylideneacet0acetic acid ethyl ester, 7 -bromonaphth-l-ylideneacetoacetic acid methyl ester, quinol-2-ylmethylideneacetoacetic acid methyl ester, quinol-3-ylmethylideneacetoacetic acid methyl ester, quinol-4-ylmethylideneacetoacetic acid ethyl ester, quniol-8-ylmethylideneacetoacetic acid ethyl ester, isoquinol-l-ylmethylideneacetoacetic acid methyl ester,

isoquinol-3-ylmethylideneacetoacetic acid methyl ester.

a-pyridylmethylideneacetonacetic acid ethyl ester,

a-pyridylmethylideneacetoacetic acid ethyl ester,

a-pyridylmethylideneacetoacetic acid allyl ester,

a-pyridylmethylideneacetoacetic acid cyclohexyl ester, B-pyridylmethylideneacetoacetic acid B-methoxyethyl ester,

y-pyridymethylideneacetoacetic acid methyl ester,

6-methyl-pyridylmethylideneacetoacetic acid ethyl ester,

4,6 -dimethoxypyrimid-S-ylmethylideneacetoacetic acid ethyl ester,

then-2-ylmethylideneacetoacetic acid ethyl ester,

fur-2-ylmethylideneacetoacetic acid allyl ester,

pyrr-2-ylthylideneacetoacetic acid methyl ester,

nitrobenzylidenepropionyl acid ethyl ester,

a-pyridylmethylidenepropionylacetic acid ethyl ester,

oz-pyridylmethylidenepropionylacetic acid methyl ester,

a-pyridylmethylideneacetylacetone,

2-, 3- or 4-methoxybenzylideneacetoacetic acid ethyl ester,

2-, 3- or 4-methoxybenzylideneacetylacetone.

Z-methoxybenzylideneacetoacetic acid allyl ester.

2-methoxybenzylideneacetoacetic acid allyl ester, 2-methoxybenzylideneacetoacetic acid propargyl ester,

Z-methoxybenzylideneacetoacetic acid B-methoxyethyl ester,

Z-isopropoxybenzylideneacetoacetic acid ethyl ester,

3-butoxybenzylideneacetoacetic acid methyl ester,

3,4,5-trimethoxybenzylideneacetoacetic acid allyl ester,

2-methylbenzylidenepropionylacetic acid methyl ester,

2-, 3- or 4-methylbenzylideneacetoacetic aid ethyl ester,

2-methylbenzylideneacetoacetic acid ,B-methoxyethyl ester,

2-methylbenzylideneacetoacetic acid B-propoxyethyl ester,

2-methylbenzylideneacetylacetone,

3,4-dimethoxy-5-bromobenzylideneacetoacetic acid ethyl ester,

2-, 3- or 4-chlorobenzylideneacetoacetic acid ethyl ester,

2-, 3- or 4-bromobenzylideneacetoacetic acid ethyl ester,

2-, 3- or 4-fluor0benzylideneacetoacetic acid ethyl ester,

Z-t'luorobenzylideneacetoacetic acid methyl ester,

3-chlorobenzylideneacetylacetone,

3-chlorobenzylidenepropionylacetic acid ethyl ester,

3-chlorobenzylideneacetoacetic acid ethyl ester,

2-chlorobenzylideneacetoacetic acid allyl ester,

2-, 3- or 4-trifluoromethylbenzylideneacetoacetic acid isopropyl ester,

3-trifluoromethylbenzylideneacetoacetic acid methyl ester,

Z-carbethoxybenzylideneacetoacetic acid methyl ester,

4-carboisopropoxybenzylideneacetoacetic acid isopropyl ester, and

4-carbomethoxybenzylideneacetoacetic acid allyl ester.

The cyclic enamino carbonyl reactants are similarly known or can be readily produced according to known methods, see for example Barnikow et al., Chem. Ber. 100, 166i (1967). Typical of these reactants are the following:

2-carbethoxymethylidenepyrrolidine,

2-carbomethoxymethylidenepyrrolidine,

2-carbisopropoxymethylidenepyrrolidine, 2-carballyl0xmethylidenepyrrolidine, 2-acetylmethylidenepyrrolidine,

Z-carbethoxymethylidenepiperidine,

2-carbomethoxymethylidenepiperidine,

2-acetylmethylidenepiperidine, 2-acetylmethylidenehexahydroazepine, 2-carbethoxymethylidenehexahydroazepine, 2-carbomethoxymethylidenehexahydroazepine, 2-acetylmethylideneimidazolidine, 2-carbethoxymethylideneimidazolidine, 2-carbomethoxymethylideneimidazolidine,

Z-carbethoxymethylidene-l-methylimidazolidine,

2-carbisopropoxymethylideneimidazolidine,

2-carballyloxymethylideneimidazolidine, 2-acetylmethylideneoxazolidine, 2-carbomethoxyideneoxazolidine, 2-carbethoxymethylideneoxyzolidine,

2 -acetylmethylideneperhydro-l ,3-oxazine,

2carbethoxymethylideneperhydro-1,3 -oxazine,

2-acetylmethylidenethiazolidine, 2-carbethoxymethylidenethizaolidine, and

Compounds Z-carbethoxymethylideneperhydro-l,3-thiazine.

In addition to these mentioned in the examples, the following are also important new compounds:

5-methyl-7-(2-nitrophenyl)-2, 3,7-trihydrothiazolo- [1,2 -a]pyridine-6,8dicarboxylic acid dimethyl ester,

6-methyl-4-(2-nitrophenyl)-l,2 -pentamethylenel,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester, and

5-methyl-7-(2nitrophenyl)-1,2,3,7- tetrahydroindolizine-6,8-dicarboxylic acid 6-methyl ester S-ethyl ester.

As noted above, the compounds of the present invention demonstrate the ability to reduce blood pressure and to effect a dilation of the coronary vessels They can accordingly be used where either or both of these effects are desired. Thus upon parenteral, oral or sublingual administration, the compounds produce a distinct and long lasting dilation of the coronary vessels which is intensified by a simultaneous nitrite-like effect of reducing the load on the heart. The effect on heart metabolism is thus one of energy saving. In addition, the compounds lower the blood pressure of normotonic and hypertonic animals and can thus be used as antihypertensive agents. These properties can be conveniently observed in well known laboratory models. Thus for example the coronary vessel dilation effect can be observed by measuring the increase in oxygen saturation in the coronary sinus in the narcotized, heart catheterized dog, as shown in the following table:

I.V. Dose (mg/kg) A 71 saturation phenyI)-2 ,3 .7-trihydropyridinc-6.8-dicarboxylic acid diethyl eter -methyl-7-[2-cyanophenyl)-2.3.7-trihydropyridine-6,8-dicarboxylic acid diethyl ester 5-methyl-7-(3'chloropyridine-6,8-dicarboxylic acid diethyl ester 5-methyl-7-( 3-nitr0- phenyl)-2,3,7-trihydro thiazolol 1 2a]- pyridine-6,8-dicarhoxylic acid diethyl ester phenyl )-2,3 .7-trihydrooxazolol 1,2-a lpyridine-6,8-dicarboxylic acid diethyl ester 5-methyI-7-(3-nitrophenyl)-2,3 .7-trihydrooxazolo[ l ,2alpyridine- 6,8-dicarboxylic acid diethyl ester 5-methyl-7-(2-methylphenyl )-2.3 .7-trihydr0- oxazolol 1,2-a1- pyridine-6,8-dicarboxy- 6,8-dicarboxylic acid diethyl ester Continued I.V. Dose (mgkg) A() pounds snluralion (a-mcthyl-4-(l'chloro- 30 phcnyl l .Z-pcntumcthylcncl .4-dihyd ropyridinc- 3,5-dicarhoxylic acid diethyl ester 6 methyl-4-(2'trifluoromethylphenyltLZ-pentamethylene-l .4-dihydropyridine-35-dicarboxylic acid 3-methyl ester 5- ethyl ester 6-methyl-4-( Z-trifluoromethylphenyl )-l,2-pentamethylene-1.4dihydropyridine-3.Sdicarboxylic acid diethyl ester 5-methyl-7-(3-nitro- 3.0 phenyl)-8-acctyl-1.2.3.7- tetrahydroindolizine-(acarhoxylic acid ethyl ester 5-methyl-7-(3-nitrophenyl)l.2.3.7-tctra hydroindolizineolidicarboxylic acid 6- methyl ester S-ethyl ester 5-methyl-7-(2-methyl 5.0 2| phenyl)-l.2.3.7'tetrahydroindolizinc-6.8- dicarboxylic acid 1 diethyl ester 5-methyl-7-(3-nitrophenyl)-l,2,3.7-tetrahydroimidazolo[l,2-a]- pyridine-6,8-dicarb0xylic acid o-propargyl ester 8-ethyl ester Returned to normal 0 values (hours) The foregoing values do not necessarily correspond to the lowest dose at which a clearly detectable rise is observed in the oxygen saturation in the coronary sinus. Thus 6-methyl-4-(3-nitrophenyl)-1,Z-pentamethylene-1 ,4-dihydropyridine-3 ,5 -dicarboxylic acid, 6-methyl-4-(2-trifluoromethylphenyl)-1,2- pentamethylene-l ,4-dihydropyridine-3 ,S-dicarboxylic acid 3-methyl ester-S-ethy'l ester, and 6 methyl-4*(3- nitrophenyl)-1 ,Z-pentamethylene-l ,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester- 5 methyl ester produ e such a rise at I.V. doses as low as 0.2, 0.3 and 0,5 mg/kg, respectively.

The hypotensive activity of the present compoundscan be observed by measuring the blood pressure oi hypertensive rats following peoral administration of the compounds. The following table demonstrates the dose which results in at leasta l5 mm Hg reduction in blood pressure of such animals:

Compound Dose (mg/kg) S-methylJ-t 2-cyanophenyl )-2.3 ,7-trihydrooxazolo- [1,2-2 lpyridinc-6,8-dicarhoxylic acid diethyl ester 5-methyl- 7-(Z-trifluoromethylphenyl)-l ,2.3,7- 3.1 tetrahydroimidazolo[ l.2-a]pyridine-6,8-

dicarboxylic acid diethyl ester o-methyl-4-(3-nitrophenyl)-l.Z-pentamethylene- 3.I

. I l.4-dihydropyridine-3,5-dicarboxylic acid 3- mcthyl ester S-ethyl ester (ontinued Compound Dose (mg/kg) 6-mcthyl-4-l3-nitrophenyl)-l,2-pentamethylenc l,4-dihydropyridine-3,5dicarboxylic acid 3- cthyl ester S-methyl ester 6-methyl-4-t2-cyanophenyl)-l .Z-pentamethylenel.4-dihydropyridine-3,5-dicarboxylic acid 3 methyl ester S-ethyl ester (1-mcthyl-4-(2-trifluoromethy|phenyl)- l ,2-pentamethylenel ,4-dihydropyridine l5-dicarhoxylic acid diethyl ester Sanethyl8-acety|-7-( Lcyanophenyl )-l ,2.3.7 tctrahyd roindolizine-o carboxylic acid ethyl CSICF 6-methy|-8 (Z-cyanophenyll-l.2.3.4.8-pentahydroquinolizine-7.9-dicarboxylic acid diethyl ester in dosage unit form; i.e. physically discrete units containing a predetermined amount of the drug corresponding to a fraction or multiple of the dose which is Compound Dose (mg/kg) 5-methyl-7-(Z-trifluoromethylphenyl)-l,2,3,7- tetrahydroimidazolol l.2-a]pyridinc6,8 dicarboxylic acid diethyl ester 6-methy|-4-(3-nitrophenyll-l,Z-pentamcthylencl.4-dihydropyridine-3,5-dicarboyxlic acid 3- mcthyl ester S-ethylester 6-methyl-4-(3nitrophenyl) l ,2-pentamethylene l,4-dihydropyridinc-3.S-dicarhoxylic acid 3' ethyl ester S-methyl ester 6-methyl-4-t2-cyanophenyl)-l,Z-pentamethylenel.4-dihydropyridinc-3,S-dicarhoxylic acid 3- methyl ester S-cthyl ester,

6-methyl-4-(2-trifluoromethylphenyl l ,Z-pentamethylencl .4-dihydropyridine-3,5-dicarboxylic acid diethyl ester 5-methyl-8-acetyl-7-tZ-cyanophenyU-l,2,3,7 v tetrahydroindolizine-o-carboxylic acid ethyl ester In addition to the effect on blood pressure and coronary vessels, the compounds also lower the excitability of the stimulus formation and excitation conduction system within the heart so that an antifibrillation action is observed at therapeutic doses. The tone of the smooth muscle of the vessels is also greatly reduced. This vascular-spasmolytic action can be observed in the entire vascular system as well as in more or less isolated and circumscribed vascular regions such as the central nervous system. ln addition, a strong musuclarspasmolytic action is manifested in the smooth muscle of the stomach, the intestinal tract, the urogenital tract and the respiratory system. Finally, there is some evidence that the compounds influence the cholesterol level and lipid level of the blood. These effects complement one another and the compounds are thus highly desirable as pharmaceutical agents to be used in the treatment of hypertension and conditions characterized by a constriction of the coronary blood vessels.

Pharmaceutical compositions for effecting such treatment will contain a major or minor amount, eg from 95 to 0.5%. of at least one l,4-dihydropyridine as herein defined in combination with a pharmaceutical carrier. the carrier comprising one or more solid. semisolid or liquid diluent. filler and formulation adjuvant which is non-toxic, inert and pharmaceutically acceptable. Such pharmaceutical compositions are preferably calculated to produce the desired therapeutic response. The dosage units can contain one, two, three, four or more single doses or, alternatively, one-half, third or fourth of a single dose. A single dose preferably contains an amount sufficient to produce the desired therapeutic effect upon administration at one application of one or more dosage units according to a predetermined dosage regimen, usually a whole, half, third or quarter of the daily dosage administered once, twice, three or flour times a day. Other therapeutic agents can also be present.

Although the dosage and dosage regimen must in each case be carefully adjusted, utilizing sound professional judgment and considering the age, weight and condition of the recipient, the route of administration and the nature and gravity of the illness, generally the daily dose will be from about 0.05 to about 10 mg/kg, preferably 0.1 to 5.0 mg/kg, when administered parenterally and from about 1 to about mg/kg, preferably 5 to 50 mg/kg, when administered orally. In some instances a sufficient therapeutic effect can be obtained at lower doses while in others, larger doses will be required.

Oral administration can be effected utilizing solid and liquid dosage unit forms such as powders, tablets, dragees, capsules, granulates. suspensions, solutions and the like.

Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate as for example starch, lactose, sucrose, glucose or mannitol. Sweetening, flavoring, preservative, dispersing and coloring agents can also be present.

Capsules are made by preparing a powder mixture as described above and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.

Tablets are formulated for example by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A-

powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally with a binder such as carboxymethyl cellulose, an alginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acacia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the resulting imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid. a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The midicaments can also be com bined with free flowing inert carriers and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous sucrose solution while elixirs are prepared through the use ofa nontoxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a nontoxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol esters, preservatives, flavor additives such as peppermint oil or saccharin, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particu' late material in polymers, wax or the like.

Parenteral administration can be effected utilizing liquiddosage unit forms such as sterile solutions and suspensions intended for subcutaneous, intramuscular or intravenous injection. These are prepared by suspending or dissolving a measured amount of the compound in a nontoxic liquid vehicle suitable for injection such as an aqueous or oleaginous medium and sterilizing the suspension or solution. Alternatively a measured amount of the compound is placed in a vial and the vial and its contents are sterilized and sealed. An accompanying vial or vehicle can be provided for mixing prior to administration. Nontoxic salts and salt solu- .tions can be added to render the injection isotonic. Stabilizers, preservatives and emulsifiers can also be added.

The following examples will serve to further typify the nature of the present invention through the presentation of specific embodiments. These examples should not be construed as a limitation on the scope of the invention since the subject matter regarded as the invention is set forth in the appended claims.

EXAMPLE 1 HaCaOOC Upon boiling a solution of 9.5 g of 2-trifluoromethylbenzylideneacetoacetic acid ethyl ester and 6.2 g of 2- carbethoxymethylidenethiazolidine in 60 ml of ethanol for 8 hours, 5-methyl-7-(2-trifluoromethylphenyl)- 2,3,7-trihydrothiazolol-trihydrothiazolo[ l,2-a]- pyridine-6,8-dicarboxylic acid diethyl ester of melting point 107 (ethyl acetate/petroleum ether) is obtained. Yield: 57% of theory.

Example 2 C o o C 2H5 Upon heating a solution of 7.8 g of Z-methylbenzylideneacetoacetic acid ethyl ester and 5.8 g of 2- carbethoxymethylidenethiazolidine in ml of isopropanol for 10 hours, 5-methyl-7-(2-methylphenyl) 2,3,7-trihydrothiazolo[ l ,2-a]-pyridine-6,8- I dicarboxylic acid diethyl ester of melting point 158 (alcohol) is obtained.

Yield: 66% of theory.

Example 3 Heating a solution of 8.l g of 2- cyanobenzylideneacetoacetic acid ethyl ester and 5.7 g of 2-carbethoxymethylidenethiazolidine in ml of ethanol for 6 hours yields -methyl-7-( 2-cyanophenyl)- 2.3,7-trihydrothiazolo[ l .2-a]pyridine-6,8-dicarboxylic acid diethyl ester of melting point 206 (ethanol). Yield: 84% of theory.

Example 4 Upon heating a solution of 8.4 g of 3- chlorobenzylideneacetoacetic acid ethyl ester and 5.7 g of 2-carbethoxymethylidenethiazolidine in 50 ml of ethanol for 6 hours, 5-methyl-7( 3-chlorophenyl)-2,3,7- trihydrothiazolol l ,2-a]pyridine-6,8-dicarboxylic acid diethyl ester of melting point 109 (ethyl acetate/petroleum ether) is obtained.

Yield: 7l/r of theory.

EXAMPLE 5 I (IOOG lh.

l CI I3 Boiling a solution of 8.8 g of 3- nitrobenzylideneacetoacetic acid ethyl ester and 5.7 g of 2-carbethoxymethylidenethiazolidine in 50 ml of ethanol for 6 hours yields 5-meth yl-7-(3-nitrophenyl)- 2,3,7-trihydrothiazolo[ l ,2-a]-pyridine-6,8- dicarboxylic acid diethyl ester of melting point 143 (ethanol).

Yield: 68% of theory.

EXAMPLE 6 Heating a solution of 8.l g of 2- cyanobenzylideneacetoacetic acid ethyl ester and 5.2 g of 2-carbethoxymethylideneoxazolidine in 50 ml of ethanol for 8 hours yields 5-methyl-7-(2-cyanophenyl)- 2,3,7-trihydrooxyozolo[ l ,2-a]pyridine-6,8- dicarboxylic aciddiethyl ester of melting point 199 (alcohol).

Yield: 51% of theory.

EXAMPLE 7 I OOCHI EXAMPLE 8 Upon heating a solution of 7.7 g of Zmethylbenzylideneacetoacetic acid ethyl ester and 5.2 g of 2- carbcthoxymethylideneoxazolidine in 50 ml of ethanol for 8 hours, 5-mcthyl-7-(2-methylphenyl)-2.3.7- trihydrooxazolol l.Z-a]pyridine-6.8-diearboxylic acid diethyl ester of melting point (ethyl acetate/pctroleum ether) is obtained.

Yield: 59% of theory.

EXAMPLE 9 N mogooc Boiling a solution of 8.4 g of 3- chlorobenzylideneacetoacetic acid ethyl ester and 5.2 g of 2-carbethoxymethyldieneoxazolidine in 50 ml of glacial acetic acid for 8 hours yields'5-methyl-7-(3- chlorophen'yl)-2,3,7-trihydrooxazolo[ l ,2-a l-pyridine- 6,8-dicarboxylic acid diethyl ester of melting point 1 10 (ethyl acetate/petroleum ether). Yield: 66% of theory.

EXAMPLE l0 COOCzHs Upon heating a solution of 6 g. ethylideneacetoacetic acid ethyl ester and 6 g of 2-carbethoxymethylideneimidazolidine in 50 mlof ethanol for 10 hours, 5,7dim'ethyl-1,2,3,7-tetrahydroimidazolo[1,2- a]pyridine-6,S-dicarboxylic -dimethyl-diethyl ester of melting point 138 (ethanol) is obtained.

Yield: 5871 of theory.

EXAMPLE 11 0001115 OEN H -N 11 O CIhCI'IgOO C- N Upon heating a solution of 9.8 g of 3- nitrobenzylideneacetoacetic acid B-methoxyethyl ester and 5.2 g of 2-carbethoxymethylideneimidazolidine in 60 ml of alcohol for 6 hours, 5-methyl-7-(3- nitropheny1)-1,2,3,7-tetrahydroimidazolo[1,2-a]- pyridine-6,8-clicarboxylic acid 6-(B-methoxyethyl) ester 8-ethyl ester of melting point 126 127 (alcohol) is obtained.

Yield: 63% of theory.

EXAMPLE 12 mowed-K N-/ Upon heating a solution of 5.3 g of benzaldehyde, 6.5 g of acetoacetic acid ethyl ester and 7.8 g of 2carbethoxymethylideneimidazolidine in 50 ml of ethanol for 6 hours, 5-methyl-7-phenyl- 1 ,2,3,7- tetrahydroimidazolo[1,2-a]pyridine-6,8-dicarboxylic acid diethyl ester of melting point 165(alcoho1) is obnitrobenzylideneacetoacetic acid ethyl ester and 5.2 g of 2-carbethoxymethylideneimidazolidine in'50 ml of alcohol for 6 hours yields 5-methyl-7-(3nitropheny|)- l2.3.7-tetrahydroimidazolo[1.2-a]pyridine-6,8- dicarhoxylic acid diethyl ester of melting point 159 (alcohol/dimethylformamide).

Yield: 6871 of theory.

EXAMPLE 14 H pooogrrs OQN- \V\ 1nooo N-- Boiling a solution of 7.8 g of 3-nitrobenzylideneacetylacetone and 5.2 g of 2-carbethoxymethylideneimidazolidine in 50 ml of glacial acetic acid for 6 hours yields 5-methyl-6-acetyl-7-(3-nitrophenyl)- 1,2,3,7-tetrahydroimidazolo[1,2-a]-pyridine-8- carboxylic acid ethyl ester of melting point (etha nol).

Yield: 54% of theory.

EXAMPLE 15 Upon heating a solution of 9.5 g of 2-trifluoromethylbenzylideneacetoacetic acid ethyl ester and 5.2 g of 2- carbethoxymethylideneimidazolidine in 50 ml of ethanol for 6 hours, 5-methyl-7-(2-trifluoromethylphenyl)- 1,2,3,7-tetrahydroimidazolo[1,2-a]-pyridine-6,8- dicarboxylic acid diethyl ester of melting point 137 (alcohol) is obtained.

Yield: 63% of theory.

EXAMPLE 16 Boiling a solution of 7.7 g of Z-methylbenzylideneacetoacetic acid ethyl ester and 5.2 g of 2- carbethoxymethylideneimidazolidine in 50 ml of ethanol for 10 hours yields 5-methy1-7-(Z-methylphenyl)- 1.23.7-tetrahydroimidazolo[1,2-a]-pyridine-6,8- dicarboxylic acid diethyl ester of melting point 202 (alcohol). 1

Yield: 69% of theory.

EXAMPLE 17 COOCQHE 1r HsC2OOC Boiling a solution of 8.4 g of 2 chlorobenzylideneacetoacetic acid ethyl ester and 5.2

g of 2-carbethoxymcthylideneimidazolidine in 50 ml of ethanol for 8 hours yields 5-pyridinc-6.8 -dicarboxylic acid diethyl ester of melting point 198% (alcohol). Yield: 59% of theory.

EXAMPLE 18 COO 0111;,

H5020 O C Upon heating a solution of 8.4 g of 3- chlorobenzylideneacetoacetic acid ethyl ester and 5.2 g of 2-carbethoxymethylideneimidazolidine in 50 ml of ethanol for 8 hours, S-methyl-7-(3-chlorophenyl- 1,2,3,7-tetrahydroimidazolol l ,2-a]pyridine-6.8- dicarboxylic acid diethyl ester of melting point 137 (alcohol) is obtained.

Yield: 60% of theory.

EXAMPLE 19 Boiling a solution of 6.9 g of 2- furfurylideneacetoacetic acid ethyl ester and 5.2 g of 2-carbethoxymethylideneimidazolidine in 50 ml of ethanol for 8 hours yields 5-methyl-7-(2-fury1)-1,2.3,7- tetrahydroimidazolo[1,2-a]pyridine-6.8-dicarb0xylic acid diethyl ester of melting point 164 (ethanol). Yield: 65% of theory.

EXAMPLE 20 EXAMPLE 21 Boling a solution of 8.7 g of 3- nitrobenzylideneacetoacetic acid ethyl ester and 5.2 g of 2-carbethoxymethylidene-1-methylimidazolidine in NO: UOOUzlIs I Clla j/W N N H C2000 50 ml of alcohol for 6 hours yields 1,5-dimethy1-7-(3- nitrophenyU-l,2,3,7-tetrahydroimidazolo-l1,2- a]pyridine-6.8-dicarboxylic acid diethyl ester (oil). Yield: 69% of theory.

EXAMPLE 22 coocnr.

' it \/k/ l (y /Y nacooo CH3 Upon heating a solution of 7.1 g of 3-nitro-6- chlorobenzylideneacctoacetic acid methyl ester and N H5020 0 C Upon heating a solution of 5.4 g of pyridin-2- aldehyde, 6.5 g of acetoacetic acid ethyl ester and 5.2 g of Z-carbethoxymethylideneimidazolidine in 50 ml of ehtanol for 6 hours, 5-methyl-7-(a-pyridyl)-1,2,3,7- tetrahydroimidazolo[ l ,2-a]pyridine-6,8-dicarboxylic acid diethyl ester of melting point 191 (isopropanol) is obtained.

Yield: 46% of theory.

3.9 of Z-carbethoxymethylideneimidazolidine in 50 ml of ethanol for 8 hours. 5-methyl-7-(3-nitro-6- chlorophenyl)-l .2.3.7-tetrahydroimidazolo-l 1,2- a]pyridine-6,8dicarboxylic acid 6-methyl ester 8-ethyl ester of melting point 182 (alcohol) is obtained. Yield: of theory.

nitrobenzylideneacetoacetic acid methyl ester and 5.2 g of 2-carbethoxymethylideneimidazolidine in 50 ml of ethanol for 6 hours, 5- methyl-7-(2-nitrophenyl)- l,2,3,7-tetrahydroimidazolol l ,2-a ]pyridine-6.8- dicarboxylic acid 6-methyl ester 8-ethyl ester of melting point 185 is obtained.

EXAMPLE 24 ()0 OCIIH H5020 O C- Upon boiling a solution of 7.8 g of ethylideneacetoaceticacid ethyl ester and 8.5 g of 2-carbomethyoxymethylidenehexahydroazepine in 50 ml of alcohol for 6 hours, 4,6-dimethyl-1,2-pentamethylene-l ,4- dihydropyridine-3,5-dicarboxylic acid 3-methyl ester S-ethyl ester of melting point 70 (ethyl acetate/petroleum) is obtained.

Yield: 57% of theory.

EXAMPLE 25 C OCI-Is H (W moooo J Upon boiling a solution of 8.3 g of 3- nitrobenzylideneacetoacetic acid methyl ester and 5.7 g of 2-carbomethoxymethylidenehexahydroazepine in 50 ml of glacial acetic acid for 8 hours, 6-methyl-4-(3- nitrophenyl )-1 ,2-pentamethylene-l ,4-dihydropyridine 3,5-dicarboxylic acid dimethyl ester of melting point 98 (ethyl acetate/petroleum ether) is obtained. Yield: 68% of theory.

EXAMPLE 26 HsUzOOC N Heating a solution of 8.8 g of 3- nitrobenzylideneacetoacetic acid ethyl ester and 5.6 g of 2-carbomethoxymethylidenehexahydroazepine in 50 ml of ethanol for 6 hours yields 6-methyl-4-(3- nitrophenyl)-l ,2-pentamethylene'1,4-dihydropyridine- 3.5-dicarboxylic acid 3-methyl ester S-ethyl ester of melting point 75 (ethyl acetate/petroleum ether). Yield: 56% of theory.

EXAMPLE 27 COOCzHr H l H3000 o N After boiling a solution of 8.3 g of 3- nltrobenzylideneacetoacetic acid methyl ester and 61. g of 2-carbenthoxymethylidenehexahydroazepine in 50 ml of alcohol for 8 hours, 6-methyl-4-(3nitrophenyl)- 1,2-pentamethylene-1,4-dihydropyridinen-3,5-

dicarboxylic acid 3- ethyl ester S-methyl ester of melting point C (ethyl acetate/petroleum ether) is ob tained.

Yield: 62% of theory.

EXAMPLE 28 C O O C2115 II I WW HaCOC N Upon heating a solution of 7.6 g of 3- nitrobenzaldehyde, 5.0 g of acetylacetone and 9.1 g of 2-carbethoxymethylidenehexahydroazepine in 50 ml of ehtanol for 8 hours, 6-methyl-5-acetyl-4(3 nitropheny1)-1 ,2-pentamethylene-1 ,4-dihydropyridine- 3-carboxylic acid ethyl ester of melting point 91 (alcohol/water) is obtained.

cyanobenzylidineacetoacetic acid ethyl ester and 5.6 g of2-carbomethoxymethylidenehexahydroazepine in 50 ml of ethanol for 8 hours, 6methyl-4(2-cyanophenyl 1,2pentamethylene-1,4-dihydropyridine-3.5- dicarboxylic acid 3-methyl ester S-ethyl ester of melt ing point 154 (alcohol) is obtained.

Yield: 61% of theory.

EXAMPLE 3() II 1 IIaUeOOC Boiling a solution of 8.1 g of 2- cyanobenzylideneacetoacetic acid ethyl ester and 6.1 g of 2-carbethoxymethylidenehexahydroazepine in 50 ml of ethanol for 6 hours yields 6-methyl-4-(2- cyanophenyl)-l ,2-pentamethylene-1 ,4- dihydropyridine-3,S-dicarboxylic acid diethyl ester of melting point 134 (ethyl acetate/petroluem ether). Yield: 54% of theory.

EXAMPLE 31 COOCH:

Upon boiling a solution of 8.4 g of 2- chlorobenzylideneacetoacetic acid ethyl ester and 5,6 g of 2-carboemthoxymethylidenehexahydroaepine in 50 ml of ethanol for 6 hours, 6-methyl-4-(2- chlrophenyl)-l,2-pentamethylene-l,4- dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-ethyl ester of melting point 123 (ethanol) is obtained.

Yield: 50% of theory.

EXAMPLE 32 COOCH:

Upon heating a solution of 7.7 g of 2-methylbenzylideneacetoacetic acid ethyl ester and 5.6 g of 2- carbomethyoxymethylidenehexahydroazepine in 50 ml of ethanol for 8 hours. 6-methyl4-(2-methylphenyl)- l,2-pentamethylene-l ,4-dihydropyridine-3,5- dicharboxylic acid 3-methyl ester S-ethyl ester of melting point 130 (alcohol) is obtained.

chlorobenzylideneacetoacetic acid ethyl ester and 6.1 g of 2-carbethoxymethylidenehexahydroazepine in 50 ml of glacial acetic acid for 6 hours yields 6-methyl4- (3-chlorophenyl)-l,2-pentamethylene-l,4- dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point l00 (ethyl acetate/petroleum ether). Yield: 65% of theory.

EXAMPLE 34 After boiling a solution of 9.1 g of 2-trifluoromethylbenzylideneacetoacetic acid ethyl ester and 5.6 g of 2- caromethoxymethylidenehexahydroazepine in 50 ml of ethanol for 8 hours, 6-methyl-4-(2- trifluoromethylphenyl l ,Z-pentamethylenel ,4- dihydropyridine-3,S-dicarboxylic acid 3-methyl ester 5-ethyl ester of melting point 1 1 1 (ethyl acetate/petroleum ether) is obtained.

Yield: 76% of theory.

EXAMPLE 35 Heating a solution of 9.1 g of 2-trifluoromethylbenzylidene'acetoacetic acid ethyl ester and 6.1 g of 2- carbethoxymethylidenehexahydroazepine in 50 ml of ethanol for 10 hours yields 6-methyl-4-(2- trifluoromethylphenyl)-l,2-pentamethylene-l,4- dihydropyridine3,S-dicarboxylic acid diethyl ester of melting point 104 (alcohol/water).

Yield: 71% of theory.

EXAMPLE 36 Boiling a solution of 8.8 g of 3- nitrobenzylideneacetoacetic acid ethyl ester and 4.6 g of 2 -acetylmethylidenepyroolidine in 50 ml of ethanol for 6 hours yields 5-methyl-7-(3-nitrophenyl )-8-acetyll,2,3,7-tetrahydroindolizine-6-carboxylic acid ethyl ester of melting point l6l (isopropanol).

Yield: 72% of theory.

EXAMPLE 37 COCIH l CII;

Upon heating a solution of9.4 g of 2-trifluoromethyl benzylideneacetoacetic acid ethyl ester and 4.6 g of 2- acetylmethylidenepyrrolidine in 50 ml of glacial acetic acid for 8 hours, -methyl-8-acetyl-7-(2- trifluoromethylphenyl)-1,2,3,7-tetrahydroindolizine-6- carboxylic acid ethyl ester of melting point 126 (ethyl acetate/petroleum ether) is obtained.

Yield: 49% of theory.

Example 38 melting point 167 (ethanol) is obtained. Yield: 59% of theory.

EXAMPLE 39 IIIO? Upon boiling a solution of 8.3 g of 3- nitrobenzylideneacetoacetic acid methyl ester and 5.6 g of 2-carbethoxymethylidenepyrrolidine b in 50 ml of glacial acetic acid for 8 hours, 5-rnethyl-7-(3- nitrophenyl)-1,2,3,7-tetrahydroindolizine-6,8- dicarboxylic acid 6-methy1 ester 8-ethyl ester of melting point 120 (ethanol) is obtained.

Yield: 73% of theory.

EXAMPLE 4O II 0000- l Upon boiling a solution of 7.7 g of 2-methylbenzylideneacetoacetic acid ethyl ester and 5.6 g ofcarbethoxymethylidenepyrrolidine in 50 ml of ethanolfor 8 hours, 5-methyl-7-(2-methlphenyl)-1,2,3,7- tetrahydroindolizine-6,8-dicarboxylic acid diethyl ester of melting point 148 (alcohol) is obtained.

Yield: 62% of theory.

26 EXAMPLE 41 Upon heating a solution of 8.1 g of 2 cyanobenzylideneacetoacetic acid ester and 5.6 g of 2-carbethoxymethylidenepiperidine in 50 ml ofethanol for 6 hours, 6-methyl-8(2-cyanophenyl)-l.2.3,4,8- pentahydroquin0lizine-7,9-icarboxylic acid diethyl ester of melting point 142 (ethyl acetate/petroleum ether) is obtained.

Yield: 59% of theory.

EXAMPLE 42 CH:i

COO (3211:.

N mogooo y Boiling a solution of 7.7 g of Z-methylbenzylideneacetoacetic acid ethyl ester and 5.6 g of 2- carbethoxymethylidenepiperidine in 50 ml of ethanol for 12 hours yields 6-methyl-8(2-methy1phenyl)- 1,2,3,4,5-pentahydroquinolizine-7,9-dicarboxylic acid diethyl ester of melting piont 106 (ethyl acetate/petroleum ether).

Yield: of theory.

EXAMPLE 43 GIT:

Upon boiling a solution of7.8 g of 3-nitrobenzylideneacetylacetone and 5.7 g of 2-carbethoxymethylidenethiazolidine in 60 ml of ethanol for 7 hours. 5-methyl-6- acetyl-7-(3-nitrophenyl)-2.3,7-trihydrothiazolo[1.2 a]pyridine8-carboxylic acid ethyl ester of melting point 152 (ethyl acetate/petroleum ether) is obtained. Yield: 59% of theory.

EXAMPLE 44 27 28 Boiling a solution 9.2 g of 3- EXAMPLE 48 nitrobenzylideneacetoacetic acid isoproyl ester and 5.2 g of 2-carbethoxymethylideneimidazolidine in 60 ml of ethanol for 2 hours yields 5-methyl-7-(3-nitrophenyl)- l,2,3,7-tetrahydroimidazolo[l,2-a]-pyridine-6,8- 5 l 0000", dicarboxylic acid 6-isopropyl ester 8-ethyl ester of a melting point l36 (ethanol). f Yield: 65% of theory. /N\

EXAMPLE 45 1O C2II50OC\ N\/ N02 00002115 1% H Heating a solution of 9.0 g of (naphth-l-ylidene)- acetoacetic acid ethyl ester and 5.2 g of Z-carbcthoxymethylideneimidazolidine in 60 ml of ethanol for 6 HCECCH;OOC\ hours yields 5-methyl-7-(naphth-l-yl)-l.2,3.7- tetrahydroimidazolol l ,2-a]-pyridine-6.8dicarboxylic H3 acid diethyl ester of melting point 169 170C (ethanol). Heating a solution of 9.1 g of 3- Yeldi 52% of theory nitrobenzylideneacetoacetic acid propargyl ester and 5.2 g of 2-carbethoxymethylideneimidazolidine in 60 ml of ethanol for 6 hours yields 5-methyl-7-(3- nitrophenyl l ,2,3,7-tetrahydroimidazolo[ l,2-a]- pyridine-6,8-dicarboxylic acid 6-propargyl ester 8- ethyl ester of melting point l53 (ethanol).

Yield: 54% of theory.

EXAMPLE 46 CO O 2 15 Heating a solution of 9.7 g of 3-carbethoxybenzylideneacetoacetic acid ethyl ester and 5.2 g of 2- carbethoxymethylideneimidazolidine in 60 ml of ethanol for 6 hours yields 5-methyl-7-(3- carbethoxyphenyU-l,2:3,7-tetrahydroimidazolo[1,2- a]-pyridine-6,8dicarboxylic acid diethyl ester of melting point 149C (ethanol).

Yield: 69% of theory.

EXAMPLE 47 CO 0 CzH5 Boiling a solution. of 7.4 g of then-2- ylideneacetoacetic acid ethyl ester and 5.2 g of 2- carbethoxymethylideneimidazolidine in 60 ml of ethanol for 6 hours yields 5-methyl-7-(then-2-yl)-l,2,3.7- tetrahydroimidazolo[ l .2-a]-pyridine-6,8-dicarboxylic acid diethyl ester of melting point 134C (ethanol). Yield: 72% of theory.

What is claimed is:

l. A compound of the formula:

0 H ()R4 1r 1 Rd X (33m)... R- -t J wherein m is 2, 3 or 4;

R is hydrogen or lower alkyl;

each of R and R. independent of the other: is lower alkoxy, lower alkoxy(lower alkyl) or alkynyloxy having 2 to 4carbon atoms; and

R is lower alkyl; phenyl; phenyl substituted by one to three substituents selected from the group consisting of lower alkyl, trifluoromethyl. cyano, halo, nitro and carbo(lower alkoxy); pyridyl; furyl; thenyl; or naphthyl.

2. A compound according to claim 1 wherein X is 3. A compound according to claim 1 wherein X is -S.

4. A compound according to claim 1 wherein R is lower alkoxy or lower alkoxy(lower alkyl),

R is lower alkyl; phenyl; phenyl substituted by lower alkyl, trifluoromethyl, cyano, halogeno. nitro, carbo-(lower alkoxy) or nitro and chloro; naphthyl; pyridyl, furyl or thenyl; and

R is lower alkoxy or alkynyloxy having 2 carbon atoms.

5. A compound according to claim 4 wherein m is 2.

6. A compound according to claim 1 wherein R is methyl;

R is lower alkoxy or lower alkoxytlwoer alkyl);

R is methyl; phenyl; phenyl substituted by methyl. trifluoromethyl, cyano, chloro, nitro, carbethoxy or nitro and chloro; naphthyl; or thenyl;

Ris rznethoxy, ethoxy, propoxy or propargyloxy; and

m is

29 30 7. The compound according to claim 1 which is 12. The compound according to claim 1 which is CFs CN 00002115 5 o 0 0211 H K s H \l/\( 7 \Vw/ I'I5CZOOC \/N\/ Ir502oo0K/ CH3 l0 c lia 8. The compound according to claim 1 which is 13. The compound according to claim I which is H COOCzHs H 000C211;-

OzN \l/\/ W \l/\/ 11502000 /N\/ 1r50i0o0 CH: cm

9. The compound according to claim 1 which is 14. The compound according to claim 1 which is CH3 CN COOCQHa OOC-glla H K S \l/\ i 1 11502000 N\/ I 11502000- 0m (in;

10. The compound according to claim 1 which is 15. The compound according to claim 1 which is 00002115 ()OOCQIL; H S 4o 0 1i. 1 11502000 N l[5C:OOC\/ CH3 Ills ill. The compound according to claim I which is 16. The compound according to claim 1 which is N02 1702 1 SO ooo02H5 00001115 H u \l/\/ \l,/ HECEOOC" 1 c0 h\/ l CH: CH: 

1. A COMPOUND OF THE FORMULA:
 2. A compound according to claim 1 wherein X is -O-.
 3. A compound according to claim 1 wherein X is -S-.
 4. A compound according to claim 1 wherein R2 is lower alkoxy or lower alkoxy(lower alkyl), R3 is lower alkyl; phenyl; phenyl substituted by lower alkyl, trifluoromethyl, cyano, halogeno, nitro, carbo-(lower alkoxy) or nitro and chloro; naphthyl; pyridyl, furyl or thenyl; and R4 is lower alkoxy or alkynyloxy having 2 carbon atoms.
 5. A compound according to claim 4 wherein m is
 2. 6. A compound according to claim 1 wherein R1 is methyl; R2 is lower alkoxy or lower alkoxy(lwoer alkyl); R3 is methyl; phenyl; phenyl substituted by methyl, trifluoromethyl, cyano, chloro, nitro, carbethoxy or nitro and chloro; naphthyl; or thenyl; R4 is methoxy, ethoxy, propoxy or propargyloxy; and m is
 2. 7. The compound according to claim 1 which is
 8. The compound according to claim 1 which is
 9. The compound according to claim 1 which is
 10. The compound according to claim 1 which is
 11. The compound according to claim 1 which is
 12. The compound according to claim 1 which is
 13. The compound according to claim 1 which is
 14. The compound according to claim 1 which is
 15. The compound according to claim 1 which is
 16. The compound according to claim 1 which is 